Mixed Gonadal Dysgenesis: A Narrative Literature Review and Clinical Primer for the Pediatric Urologist
Lauren E. Corona, MD1, Victoria Lee, BS1, Allison Weisman, MS, CGC1, Josephine Hirsch, BS1, Ilina Rosoklija, MPH1, Jax Whitehead, MD1, Abdullah Almaghraby, MD2, Jaclyn Papadakis, PhD1, Briahna Yuodsnukis, PhD1, Diane Chen, PhD1, Courtney Finlayson, MD1, Elizabeth B Yerkes, MD1, Earl Y. Cheng, MD1, Emilie K. Johnson, MD, MPH1.
1Lurie Children's Hospital, Chicago, IL, USA, 2IWK Health System, Dalhousie University, Halifax, NS, Canada.
BackgroundMixed gonadal dysgenesis (MGD) is a difference of sex development (DSD) that is often confused with other conditions. Individuals have a 45,X/46,XY karyotype. Gonads are characterized by a streak gonad and a dysgenetic testis at varying levels of descent. Persistent Müllerian structures are typically present ipsilateral to the streak gonad (e.g. hemiuterus). There is significant phenotypic heterogeneity of the internal and external genitalia. All individuals have genital atypia, but this ranges from clitoromegaly to distal hypospadias. This phenotypic heterogeneity and different interpretations of the MGD definition have contributed to a poor understanding of MGD among pediatric urologists. MGD is one manifestation of the 45,X/46,XY karyotype. 45,X/46,XY mosaicism can also be associated with typical female (Turner syndrome with Y chromosome material) or male external genitalia. This review aims to clarify the MGD definition and to provide urologists with diagnostic and management considerations for patients with MGD. MethodsWe performed an Embase and Pubmed search for major subject headings and title/abstract keywords related to MGD. After a title/abstract review of 875 publications, 268 were further reviewed for content pertinent to: (1) Clarifying the definition of MGD, and (2) Describing the following related to the care of individuals with MGD: prenatal and neonatal evaluation and management, genital reconstruction and surgery, gonadal malignancy risk and management, fertility, gender dysphoria, puberty and long-term outcomes, and systemic comorbidities.ResultsOf the 268 articles reviewed, 100 were included. Key points and implications for each of the above topics are listed in Table 1. ConclusionsMGD exists on a wide phenotypic spectrum and management considerations reflect this heterogeneity. Care for individuals with MGD is complex, and decisions should be made in a multidisciplinary setting with psychological support.
| Topic | Articles included | Key Points | Implications |
| Definition | 31 | •MGD is characterized by atypical genitalia, a unilateral streak or absent gonad, and a unilateral (typically dysgenetic) testis •Persistent Müllerian structures are almost always present and predominate on the side ipsilateral to the streak gonad (e.g., hemi- or partially formed uterus)•Categorized as a sex chromosome DSD, associated with mosaicism of the sex chromosomes (most commonly, 45,X/46,XY)•Additional cell lines possible with one or two copies of a normal or isodiscentric Y chromosome (e.g. 45,X/46,XY/47,XYY)•MGD is NOT synonymous with 45,X/46,XY•45,X/46,XY karyotype can also be associated with:•Other DSDs•Turner syndrome with Y chromosome material (bilateral streak gonads, typical female external genitalia)•Ovotesticular DSD (unequivocal presence of both ovarian and testicular tissue)*•Partial gonadal dysgenesis (bilateral dysgenetic testes)*•Males with/without infertility (typical male external genitalia)•Most common | MGD is one manifestation of the 45,X/46,XY karyotype and is characterized by atypical genitalia with (typically) a streak gonad and a dysgenetic testis. |
| Prenatal evaluation and management | 10 | •89-95% of fetuses with antenatal detection of 45,X/46,XY karyotype via amniocentesis have a typical male phenotype at birth•If detected, families should be counseled on the range of potential phenotypes and offered additional imaging for further characterization of genitalia, but more specific postnatal management recommendations should be deferred until birth•At birth, chromosome analysis should be repeated (results not always congruent with prenatal karyotype)•False-positive rate for sex chromosomal aneuploidy with cell free DNA has recently been found to be higher than previously reported•Degree of mosaicism in the amniotic fluid is not representative of genital, gonadal, or somatic phenotype•Only the degree of gonadal mosaicism (which cannot be detected prenatally) correlates with external genital appearance | An antenatally detected 45,X/46,XY karyotype is not predictive of phenotype. Families should be offered additional imaging for evaluation of the genitalia. More specific management recommendations should be deferred until birth. |
| Neonatal and early evaluation and management | 11 | •Spectrum of physical exam findings:•Gonads: May be palpable unilaterally at various levels or bilaterally nonpalpable (intraabdominal dysgenetic testis + contralateral streak gonad)•Clitorophallus: Range from clitoromegaly to distal hypospadias. •Most commonly: Single opening for urethra and Müllerian structures, perineal division of the corpus spongiosum and ventral curvature •Müllerian cavity: Typically present proximal to the urethra, narrow and rigid•Studies to perform at birth:•Peripheral blood chromosome analysis with expanded cell count (minimum 40 cells) to confirm karyotype•Abdominopelvic ultrasound •Routine DSD labs including androgens, gonadotropins, anti-Müllerian hormone (AMH), 17-hydroxyprogesterone, and serum electrolytes•AMH/androgens + gonadotropins typical (depending on degree of testicular tissue function)•A multidisciplinary team should be involved for initial family counselling and in determining sex of rearing | A thorough history (including obstetric and familial) and physical exam are prudent. Early involvement of a multidisciplinary team is recommended. |
| Genital reconstruction & Surgery | 12 | •Early genital surgery is controversial, should focus on function over cosmesis, and should follow the ethical principles outlined for surgery in infants with other DSDs•Masculinizing options: No surgery, hypospadias repair (+/- androgen stimulation)•Feminizing options: No surgery, clitoral surgery alone, urogenital sinus repair alone, combination•Vaginal dilation should be avoided in children•Vaginoplasty in MGD is reportedly more complex secondary to the narrow and rigid Müllerian cavity•Müllerian structures: No surgery unless symptomatic | Decisions about genital reconstructive surgery should follow the ethical principles outlined for surgery in infants with other DSDs. Vaginoplasty in females with MGD is reportedly more complex secondary to the narrow and rigid Müllerian cavity. |
| Gonadal malignancy risk and management | 19 | •Risk of gonadoblastoma is uncertain and not limited to the post-pubertal population as previously suspected •Likely higher in MGD than 45,X/46,XY phenotypic males and lower than in Turner+Y females (attributed to the higher degree of gonadal maldevelopment in less masculinized individuals)•MGD is considered a higher risk DSD for development of gonadoblastoma along with other gonadal dysgenesis syndromes•Risk of malignant transformation is likely low•Shared-decision making should be used to discuss possible early gonadectomy in individuals where gonadal function (puberty, fertility) is unlikely•Retention of gonad(s) without gonadectomy:•For undescended testes, orchidopexy should be performed (+/- biopsy)•For scrotal testes, surveillance is recommended•Biopsy and imaging cannot reliably rule out neoplasm in these settings | MGD is considered a higher risk DSD for development of gonadoblastoma, and a shared decision-making approach should be used to discuss possible early gonadectomy in individuals where gonadal function (puberty, fertility) is unlikely. |
| Fertility | 7 | •Experimental gonadal tissue cryopreservation (GTC) at the time of gonadectomy is an option offered at some institutions •Viable germ cells are seen at time of gonadectomy with an inverse association between number recovered and age•Future fertility from GTC will require both presence of germ cells and technological advancement to allow for maturation •Potential for fertility with assisted reproductive technology (egg donation, testicular sperm extraction) is rare but exists, needs to be weighed against possibility of decreasing germ cells with age | Fertility with use of assisted reproductive technology is rare but possible, and gonadal tissue cryopreservation (GTC) at time of gonadectomy is still in experimental phases but should be discussed. |
| Gender dysphoria | 7 | •Incidence of gender dysphoria is thought to be at least 12% •Gender dysphoria has not been reported in individuals assigned male gender | Gender dysphoria is reported in >10% but has not been reported in individuals assigned male sex of rearing. |
| Puberty & Long-term outcomes | 16 | •When gonads have been retained, onset of spontaneous testosterone-mediated puberty occurs in most•Impaired progression of puberty and declining gonadal function is typical •Hormones should be initiated at pubertal age with sperm cryopreservation and/or gonadectomy with GTC re-addressed if gonads remain in situ | Gonadal hormone production during puberty is typically limited to testosterone from the dysgenetic testis and commonly requires hormonal augmentation. |
| Systemic comorbidities | 9 | •Turner-associated systemic comorbidities including short stature, hearing loss, hypothyroidism, cardiac and renal anomalies, and abnormal neuropsychiatric evaluation are reported at a higher rate than the general population irrespective of phenotype•Routine Turner-like surveillance is recommended | Routine Turner-like surveillance is recommended in individuals with MGD. |
Table 1. Review topics with number of articles included, key points, and implications for the pediatric urologist regarding mixed gonadal dysgenesis.*Depending on the consensus statement. Partial gonadal dysgenesis is classically associated with 46,XY and is categorized only in this setting in the modern consensus statements. Ovotesticular DSD is more typically seen with a 46,XY or 46,XX karyotype. Some have proposed excluding the 45,X/46,XY karyotype from the ovotesticular designation, as has been done in some consensus statements.
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